ABSTRACT
Transient Receptor Potential channels are exquisite molecular transducers of multiple physical and chemical stimuli, hence the raising interest to study their relevance to Sensory Biology. Here we discuss a number of aspects of the biophysical and pharmacological properties of TRP channels, which we consider essential for a clear understanding of their sensory function in vivo. By examining concrete examples extracted from recent literature we illustrate that TRP channel research is a field in motion, and that many established dogmas on biophysical properties, drug specificity and physiological role are continuously reshaped, and sometimes even dismantled.
Subject(s)
Drug Discovery/methods , Sensation/physiology , Transient Receptor Potential Channels/chemistry , Transient Receptor Potential Channels/physiology , Humans , Transient Receptor Potential Channels/agonists , Transient Receptor Potential Channels/antagonists & inhibitorsABSTRACT
Peripheral interactions between nociceptive fibers and mast cells contribute to inflammatory pain, but little is known about mechanisms mediating neuro-immune communication. Here we show that metalloproteinase MT5-MMP (MMP-24) is an essential mediator of peripheral thermal nociception and inflammatory hyperalgesia. We report that MT5-MMP is expressed by CGRP-containing peptidergic nociceptors in dorsal root ganglia and that Mmp24-deficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions. Consistently, mutant peptidergic sensory neurons hyperinnervate the skin, a phenotype that correlates with changes in the regulated cleavage of the cell-cell adhesion molecule N-cadherin. In contrast to basal nociception, Mmp24(-/-) mice do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. Collectively, our findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that this metalloproteinase may be a target for pain control.